CA2191983A1 - 2,4,6-triiodo-5-substituted-amino-isophthalate esters useful as x-ray contrast agents for medical diagnostic imaging - Google Patents
2,4,6-triiodo-5-substituted-amino-isophthalate esters useful as x-ray contrast agents for medical diagnostic imagingInfo
- Publication number
- CA2191983A1 CA2191983A1 CA002191983A CA2191983A CA2191983A1 CA 2191983 A1 CA2191983 A1 CA 2191983A1 CA 002191983 A CA002191983 A CA 002191983A CA 2191983 A CA2191983 A CA 2191983A CA 2191983 A1 CA2191983 A1 CA 2191983A1
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- Prior art keywords
- triiodo
- alkyl
- compound
- ray contrast
- isophthalate
- Prior art date
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- Abandoned
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Compounds having structure (I) wherein Q is (II); n is an integer from 0 to 20; R1 is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl or acetamidoalkyl; R2, R3, R4 and R5 are independently H, alkyl, fluoroalkyl, halogen, hydroxy, acylamino, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido; R6 is alkyl, cycloalkyl, aryl or aralkyl; and R7 is H or -COR6 are useful as contrast agents in medical diagnostic x-ray imaging compositions and methods.
Description
2 1 9 1 9 8 3 ~ /400 2,4,6-TRIIODO-5-SUB~ lu1~-AMINO-ISOPHTHALATE ESTERS USEFUL
AS X-RAY CONTRAST AGENTS FOR MEDICAL DIAGNOSTIC IMAGING
FIELD OF INVENTION
S
This invention relates to iodinated aroyloxy esters which find particular utility as x-ray contrast agents in medical diagnostic imaging.
BACKGROUND OF THE INVENTION
X-ray imaging is a well known and extremely valuable tool for the early detection and diagnosis of :~
various disease states in the human body. The use of contrast agents for image enhancement in medical x-ray imaging procedures is widespread. An excellent background on iodinated and other contrast agentg for medical imaging is provided by D.P. Swanson et al, ph~r~ceuticals in Medical I~ain~, l990, MacMillan ~hl;5hing Company.
U.S. Patent No. 3,097,228 describes derivatives of 2,4,6-triiodobenzoyloxyalkanoic acids having the structure Cl ooR4 COO~H
R
I
R~NHR2 wherein Rl is H or lower alkyl; R2 is H or lower alkanoyI;
R3 is H or lower alkanoylamino and R~ is lower alkyl. The agents are useful as x-ray contrast agents for visualizing the gall bladder (cholecystography) when administered WO96/00210 2 1 9 1 9 8 3 PCT~S9~07400 .
orally, in the~ free acid form or in the form of a non-toxic salt, or intravenously, in the form of water soluble, non-toxic salt.
Bacon et al, commonly assigned U.S. Patent S Application Serial No. 07/990,987 ~iled December 16, 1992 describes iodinated aroyloxy esters which are useful as contrast agents in x-ray imaging com~ositions and methods However, all of the compounds described by Bacon et al feature an ester group linked through a C2 or higher alkylene group to another ester group on an iodinated aromatic ring.
U.S. Patent ~o 4,364,921 describes triiodinated isophthalic acid diamides as nonionic x-ray contrast media.
All of the described compounds contain amide residues in the 3- and 5- positions of the 2,4,6-triiodoisorh~hAl;c acid.
EP-A 498,482 describes nanoparticulate x-ray contrast compositions which have proven to be extremely useful in medical imaging. The compositions comprise particles of an organic x-ray contrast agent and a surface modifier adsorbed on the surface thereo~ and have an effective average particle size of less than 400 nm. The agents can be delivered to a specific tissue or fluid site, e.g., the blood pool, liver, spleen, kidney or lymph nodes.
EP-A 498,482 describes derivatives of diatrizoate, iothalamate, metrizoate and iodipamide containing an --o--alkylene--C--wherein R' is alkyl. However, EP-A 498,482 does not suggest the 2,4,6-triiodo-5-substituted-isophthalate esters of this invention.
Il~reuv~,, it has been discovered that some of the derivatives described in EP-A 498,482 can exhibit multiple crystal forms, i.e., polymorphs, e.g., when recrystallized WO96100210 21 9 1 9 8 3 P~ 40n .
from various solvents. The reasons for this behavior are -not completely understood, but, in any event, multiple crystal forms are disadvantageous for a variety of reasons.
or example, the presence of multiple crystal forms renders scale-up problematic due to the lack of reproducibility of the results obtained, including, e.g., in chemical manufacturing and in the milling process. Furthermore, particulate contrast agents in certain in vivo applications can exhibit less than fully satisfactory solubility profiles and/or enzymatic stability, e.g., in plasma and blood.
Conse~uently, it would be highly desirable to provide poorly soluble x-ray contrast agents which exhibit a consistent and reproducible crystal morphology, and improved solubility profiles and enzymatic stability.
SUMMARY OF THE INVENTION
We have discovered and synthesized certain novel esters of 2,4,6-triiodo-5-substituted-amino-isophthalic acid which exhibit a consistent and reproducible crystal morphology, and improved solubility profiles and enzymatic stability.
More specifically, in accordance with this invention, there are provided 2,4,6-triiodo-5-substituted-2~ amino-isophthalic esters and acids having the structure I:
I.
~OOQ
R~CON ~ COOQ
WO96/00210 2 1 9 1 9 8 3 PCT~S9~07400 .
l ~ 2 R~- f R
~ .
wherein Q is n is an integer frDm 0 to 20;
Rl is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl or acetamidoalkyl;~
R2, R3~ R4 and Rs are independently H, alkyl, fluoroalkyl, halogen, hydroxy, acylamino, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido;
R6 is alkyl, cycloalkyI, aryl, or aralkyl; and R7 is H or -COR6-It is an advantageous feature of this invention that novel iodinated aroyloxy esters and acids are provided which find particular utility in x-ray contrast compositions.
It is another advantageous feature of this invention that compounds are provided having improved solubility profiles and enzymatic stability.
Still another advantageous feature of this invention is that compounds are provided which exhibit a consistent crystal morphology during purification and thus are particularly amenable to reproducible scale-up.
DESCRIPTION OF ~KE~KK~ EMBODIMENTS
In structure I above, each Q independently l ~ 2 R~--CI Rl - - - C - ~f ~ R
~5 represents a K~ R3 group.
n represents an integer from 0-20 inclusive. In preferred embodiments, n is 0, l, 2, 3 or 4.
WO96/00210 2 ~ 9 1 983 PCTNS95/07400 R1 represents H; linear or branched alkyl, preferably rrnt A ininr from l to 2 a, more preferably from 1 to 14, and most preferably from l to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like; fluoroalkyl, the alkyl portion of which is as defined above and containing from 1 to (2m + 1) fluorine atoms (where m = the number of carbon atoms in the alkyl group), such as trifluoromethyl; cycloalkyl, preferably rr,nt~;n;nr from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; aryl, preferably cnnt~in;nr from 6 to 10 carbon atoms, such as phenyl and naphthyl; aralkyl, preferably containing from 7 to 12 carbon atoms, such as benzyl; alkoxyalkyl, the alkyl portions of which preferably contain from l to 20 carbon atoms as defined for alkyl above; or acetamidoalkyl, i.e., - NH-C-alkyl wherein alkyl is as defined above.
R2, R3, R4 and R5 are independently H; linear or branched alkyl, preferably containing from 1 to 20, more --~
preferably 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like;
fluoroalkyl, the alkyl portion of which is as described above and c~r~;n;nr from 1 to (2m+1) fluorine atoms (where m = the number of carbon atoms in the alkyl group), such as trifluoromethyl; halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; acylamino, i.e., a 1~l ,R8 - C-N~g R
group; acetamidoalkyl, i.e., Y
wherein alkyl is as defined above; cyano; sulfonyl;
carboxamido; sulfonamido and the like. However, reactive substituents such as halogen, hydroxy, and acylamino are not preferred on the carbon atoms closest to the ester groups. Thus, in particularly preferred embodiments, R5 is WO96100210 2 1 9 1 9 8 3 PCT~Sg5107400 .
H, alkyl, ~luoroalkyl, acetami~oalkyl, cyano, sulfonyl, r~rhr,~mi ~n C~ sulfonamido. The reason for this is that when R5 is halogen, hydroxy or acylamino, the compounds tend to be more reactive and less useful as particulate x-ray contrast agents.
R6 represents alkyl, as defined above;
cycloalkyl, preferably containing from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyli aryl, preferably containing from 6 to 10 carbon atoms such as phenyl or naphthyl; or aralkyl, preferably containing from 7 to 12 carbon atoms, such as benzyl.
R7 represents H or -COR6, wherein R6 is as defined above.
R8 and R9 are ~n~p~n~ntly a substituent as defined for R2-R5 above, or R8 and R9, taken together with the nitrogen atom to which they are attached, represent a 4-7 membered saturated or unsaturated nitrogen containing ring such as piperidyl, piperizinyl, pyrrolidinyl, and the like The following are specific illustrative examples of preferred compounds of this invention that have been prepared:
sis-[1-(ethoxycarbonyl)propyl] 2,4, 6- triiodo-5-acetylamino-isnrhth~l~te;
sis-[1-(ethoxycarbonyl)pentyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)ethyl] 2,4,6-triiodo-5-acetylamino-isophth~l~te;
sis-[1-(ethoxycarbonyl)butyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)methyl] 2,4,6-triiodo-5-acetylamino-isophthalate.
WO96/00210 2 1 9 1 9 8 3 PCT~S95/07400 ~ -7-Preferred compounds of this invention conform to structure I above, as indicated in the Table set forth below:
CompoundR1 n R2 R3 R4 Rs R6 R7 l -C2Hs2 H H H H -CH3 H
2 -C2Hsl H H H H -CH3 H
3 -C2Hs4 H H H H -C~3 H
AS X-RAY CONTRAST AGENTS FOR MEDICAL DIAGNOSTIC IMAGING
FIELD OF INVENTION
S
This invention relates to iodinated aroyloxy esters which find particular utility as x-ray contrast agents in medical diagnostic imaging.
BACKGROUND OF THE INVENTION
X-ray imaging is a well known and extremely valuable tool for the early detection and diagnosis of :~
various disease states in the human body. The use of contrast agents for image enhancement in medical x-ray imaging procedures is widespread. An excellent background on iodinated and other contrast agentg for medical imaging is provided by D.P. Swanson et al, ph~r~ceuticals in Medical I~ain~, l990, MacMillan ~hl;5hing Company.
U.S. Patent No. 3,097,228 describes derivatives of 2,4,6-triiodobenzoyloxyalkanoic acids having the structure Cl ooR4 COO~H
R
I
R~NHR2 wherein Rl is H or lower alkyl; R2 is H or lower alkanoyI;
R3 is H or lower alkanoylamino and R~ is lower alkyl. The agents are useful as x-ray contrast agents for visualizing the gall bladder (cholecystography) when administered WO96/00210 2 1 9 1 9 8 3 PCT~S9~07400 .
orally, in the~ free acid form or in the form of a non-toxic salt, or intravenously, in the form of water soluble, non-toxic salt.
Bacon et al, commonly assigned U.S. Patent S Application Serial No. 07/990,987 ~iled December 16, 1992 describes iodinated aroyloxy esters which are useful as contrast agents in x-ray imaging com~ositions and methods However, all of the compounds described by Bacon et al feature an ester group linked through a C2 or higher alkylene group to another ester group on an iodinated aromatic ring.
U.S. Patent ~o 4,364,921 describes triiodinated isophthalic acid diamides as nonionic x-ray contrast media.
All of the described compounds contain amide residues in the 3- and 5- positions of the 2,4,6-triiodoisorh~hAl;c acid.
EP-A 498,482 describes nanoparticulate x-ray contrast compositions which have proven to be extremely useful in medical imaging. The compositions comprise particles of an organic x-ray contrast agent and a surface modifier adsorbed on the surface thereo~ and have an effective average particle size of less than 400 nm. The agents can be delivered to a specific tissue or fluid site, e.g., the blood pool, liver, spleen, kidney or lymph nodes.
EP-A 498,482 describes derivatives of diatrizoate, iothalamate, metrizoate and iodipamide containing an --o--alkylene--C--wherein R' is alkyl. However, EP-A 498,482 does not suggest the 2,4,6-triiodo-5-substituted-isophthalate esters of this invention.
Il~reuv~,, it has been discovered that some of the derivatives described in EP-A 498,482 can exhibit multiple crystal forms, i.e., polymorphs, e.g., when recrystallized WO96100210 21 9 1 9 8 3 P~ 40n .
from various solvents. The reasons for this behavior are -not completely understood, but, in any event, multiple crystal forms are disadvantageous for a variety of reasons.
or example, the presence of multiple crystal forms renders scale-up problematic due to the lack of reproducibility of the results obtained, including, e.g., in chemical manufacturing and in the milling process. Furthermore, particulate contrast agents in certain in vivo applications can exhibit less than fully satisfactory solubility profiles and/or enzymatic stability, e.g., in plasma and blood.
Conse~uently, it would be highly desirable to provide poorly soluble x-ray contrast agents which exhibit a consistent and reproducible crystal morphology, and improved solubility profiles and enzymatic stability.
SUMMARY OF THE INVENTION
We have discovered and synthesized certain novel esters of 2,4,6-triiodo-5-substituted-amino-isophthalic acid which exhibit a consistent and reproducible crystal morphology, and improved solubility profiles and enzymatic stability.
More specifically, in accordance with this invention, there are provided 2,4,6-triiodo-5-substituted-2~ amino-isophthalic esters and acids having the structure I:
I.
~OOQ
R~CON ~ COOQ
WO96/00210 2 1 9 1 9 8 3 PCT~S9~07400 .
l ~ 2 R~- f R
~ .
wherein Q is n is an integer frDm 0 to 20;
Rl is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl or acetamidoalkyl;~
R2, R3~ R4 and Rs are independently H, alkyl, fluoroalkyl, halogen, hydroxy, acylamino, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido;
R6 is alkyl, cycloalkyI, aryl, or aralkyl; and R7 is H or -COR6-It is an advantageous feature of this invention that novel iodinated aroyloxy esters and acids are provided which find particular utility in x-ray contrast compositions.
It is another advantageous feature of this invention that compounds are provided having improved solubility profiles and enzymatic stability.
Still another advantageous feature of this invention is that compounds are provided which exhibit a consistent crystal morphology during purification and thus are particularly amenable to reproducible scale-up.
DESCRIPTION OF ~KE~KK~ EMBODIMENTS
In structure I above, each Q independently l ~ 2 R~--CI Rl - - - C - ~f ~ R
~5 represents a K~ R3 group.
n represents an integer from 0-20 inclusive. In preferred embodiments, n is 0, l, 2, 3 or 4.
WO96/00210 2 ~ 9 1 983 PCTNS95/07400 R1 represents H; linear or branched alkyl, preferably rrnt A ininr from l to 2 a, more preferably from 1 to 14, and most preferably from l to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like; fluoroalkyl, the alkyl portion of which is as defined above and containing from 1 to (2m + 1) fluorine atoms (where m = the number of carbon atoms in the alkyl group), such as trifluoromethyl; cycloalkyl, preferably rr,nt~;n;nr from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; aryl, preferably cnnt~in;nr from 6 to 10 carbon atoms, such as phenyl and naphthyl; aralkyl, preferably containing from 7 to 12 carbon atoms, such as benzyl; alkoxyalkyl, the alkyl portions of which preferably contain from l to 20 carbon atoms as defined for alkyl above; or acetamidoalkyl, i.e., - NH-C-alkyl wherein alkyl is as defined above.
R2, R3, R4 and R5 are independently H; linear or branched alkyl, preferably containing from 1 to 20, more --~
preferably 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like;
fluoroalkyl, the alkyl portion of which is as described above and c~r~;n;nr from 1 to (2m+1) fluorine atoms (where m = the number of carbon atoms in the alkyl group), such as trifluoromethyl; halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; acylamino, i.e., a 1~l ,R8 - C-N~g R
group; acetamidoalkyl, i.e., Y
wherein alkyl is as defined above; cyano; sulfonyl;
carboxamido; sulfonamido and the like. However, reactive substituents such as halogen, hydroxy, and acylamino are not preferred on the carbon atoms closest to the ester groups. Thus, in particularly preferred embodiments, R5 is WO96100210 2 1 9 1 9 8 3 PCT~Sg5107400 .
H, alkyl, ~luoroalkyl, acetami~oalkyl, cyano, sulfonyl, r~rhr,~mi ~n C~ sulfonamido. The reason for this is that when R5 is halogen, hydroxy or acylamino, the compounds tend to be more reactive and less useful as particulate x-ray contrast agents.
R6 represents alkyl, as defined above;
cycloalkyl, preferably containing from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyli aryl, preferably containing from 6 to 10 carbon atoms such as phenyl or naphthyl; or aralkyl, preferably containing from 7 to 12 carbon atoms, such as benzyl.
R7 represents H or -COR6, wherein R6 is as defined above.
R8 and R9 are ~n~p~n~ntly a substituent as defined for R2-R5 above, or R8 and R9, taken together with the nitrogen atom to which they are attached, represent a 4-7 membered saturated or unsaturated nitrogen containing ring such as piperidyl, piperizinyl, pyrrolidinyl, and the like The following are specific illustrative examples of preferred compounds of this invention that have been prepared:
sis-[1-(ethoxycarbonyl)propyl] 2,4, 6- triiodo-5-acetylamino-isnrhth~l~te;
sis-[1-(ethoxycarbonyl)pentyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)ethyl] 2,4,6-triiodo-5-acetylamino-isophth~l~te;
sis-[1-(ethoxycarbonyl)butyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)methyl] 2,4,6-triiodo-5-acetylamino-isophthalate.
WO96/00210 2 1 9 1 9 8 3 PCT~S95/07400 ~ -7-Preferred compounds of this invention conform to structure I above, as indicated in the Table set forth below:
CompoundR1 n R2 R3 R4 Rs R6 R7 l -C2Hs2 H H H H -CH3 H
2 -C2Hsl H H H H -CH3 H
3 -C2Hs4 H H H H -C~3 H
-C2HsO - - H H -CH3 H
The compounds of this invention can be prepared by contacting the carboxylate of 2,4,6-triiodo-5-substituted-amino-isophthalic acid with a functionalized ester having 1--~C 2 R~ IR
--Cl--~CI ~ R
the formula Rs R
wherein X is a leaving group and n and Rl-R5 are as defined above, in a suitable solvent. Suitable leaving groups include halogen, such as Br, I and Cl, and sulfonyloxy, such as methanesulfonyloxy and toluenesulfonyloxy. The carboxylates of iodinated aromatic acids and functionalized esters useful as the starting materials in the preparation of the compounds of this invention are known compounds 2~ and/or can be prepared by techniques known in the art. For example, suitable esters include commercially available bromoester and chloroester derivatives as exemplified below.
A general reaction scheme is as follows:
?1 919~3 WO96/00210 PCT~S95/07400 .
COO
+ ~ ¦ 1 4 - I
~ C--~C~--R
RsCON ~ COO Is R3 R7+
The reaction can take place at various temperatures ranging between -78~C and 100~C, and preferably between -40~C and 50~C. Eor convenience, the reaction can take place at ambient pressure, however, higher and lower pressures are contemplated.
The reaction can take place in any suitable solvent. Suitable solvents include N,N-dimethylformamide (DME) and dimethylsulfoxide (DMSO).
The iodinated compounds can contain substituents which do not deleteriously affect the contrast ~nhAn~;ng capability of the compound. For example, the alkyl, cycloalkyl, aryl, aralkyl and alkoxy groups in structure I
above can be unsubstituted or substituted with various substituents wbich do not adversely affect the stability or efficacy of the compounds as x-ray contrast agents such as alkyl, cycloalkyl, aryl, aralkyl, alkoxy; hydroxy, acyloxy, halogen, such as chlorine, bromine and iodine, acylamino, ~ArhoAlknxy~ carbamyl and the like.
When used as an x-ray contrast agent, the compound of this invention preferably comprises at least about 35~, more preferably at least 40~ iodine by weight.
In preferred embodiments, the compounds of this invention can be formulated into particulate x-ray contrast compositions, preferably nanoparticulate x-ray contrast compositions, as described in commonly-owned EP-A ~98,482.
Preferred compounds exhibit a melting point of greater than 150~C. Such nanoparticulate compositions can be prepared by ~1 91 aQ-2 W096l00210 ~ ~ V~ wJ~1400 _g_ dispersing the compounds of the invention in a liquid =~
dispersion medium, and wet grinding the compound in the presence of rigid grinding media and a surface modifier to form the nanoparticles. Alternatively, the surface modifier can be contacted with the compound after attrition.
Preferred surface modifiers include nonionic surfactants.
In preferred embodiments, the surface modifier is a high molecular weight nonionic surfactant. Preferred surfactants include poloxamers such as Pluronic_ F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, pol ~mi n~.~, such as Tetronic_ 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, and dialkyl esters of sodium sulfosuccinic acid, such as dioctylsulfosuccinate sodium IDoSS). The concentrations of the surface modifier can vary from about 0.1-75~, preferably 1-60~, and more preferably 10-30~ by weight based on the total c~mhi n~ weight of the contrast agent and surface modifier.
In preferred embodiments, the x-ray contrast composition in the form of surface modified nanoparticles can be associated with a cloud point modifier to further enhance stability during steam heat autoclaving, i.e., the cloud point modifier can reduce particle aggregation during heat sterilization. Preferred cloud point modifiers include nonionic cloud point modifiers, such as polyethylene glycols such as PEG 400, propylene glycol, ethanol, hydroxypropylcyclodextrin and glycerol; ionic cloud point modifiers, such as those described in U.S. Patent No.
The compounds of this invention can be prepared by contacting the carboxylate of 2,4,6-triiodo-5-substituted-amino-isophthalic acid with a functionalized ester having 1--~C 2 R~ IR
--Cl--~CI ~ R
the formula Rs R
wherein X is a leaving group and n and Rl-R5 are as defined above, in a suitable solvent. Suitable leaving groups include halogen, such as Br, I and Cl, and sulfonyloxy, such as methanesulfonyloxy and toluenesulfonyloxy. The carboxylates of iodinated aromatic acids and functionalized esters useful as the starting materials in the preparation of the compounds of this invention are known compounds 2~ and/or can be prepared by techniques known in the art. For example, suitable esters include commercially available bromoester and chloroester derivatives as exemplified below.
A general reaction scheme is as follows:
?1 919~3 WO96/00210 PCT~S95/07400 .
COO
+ ~ ¦ 1 4 - I
~ C--~C~--R
RsCON ~ COO Is R3 R7+
The reaction can take place at various temperatures ranging between -78~C and 100~C, and preferably between -40~C and 50~C. Eor convenience, the reaction can take place at ambient pressure, however, higher and lower pressures are contemplated.
The reaction can take place in any suitable solvent. Suitable solvents include N,N-dimethylformamide (DME) and dimethylsulfoxide (DMSO).
The iodinated compounds can contain substituents which do not deleteriously affect the contrast ~nhAn~;ng capability of the compound. For example, the alkyl, cycloalkyl, aryl, aralkyl and alkoxy groups in structure I
above can be unsubstituted or substituted with various substituents wbich do not adversely affect the stability or efficacy of the compounds as x-ray contrast agents such as alkyl, cycloalkyl, aryl, aralkyl, alkoxy; hydroxy, acyloxy, halogen, such as chlorine, bromine and iodine, acylamino, ~ArhoAlknxy~ carbamyl and the like.
When used as an x-ray contrast agent, the compound of this invention preferably comprises at least about 35~, more preferably at least 40~ iodine by weight.
In preferred embodiments, the compounds of this invention can be formulated into particulate x-ray contrast compositions, preferably nanoparticulate x-ray contrast compositions, as described in commonly-owned EP-A ~98,482.
Preferred compounds exhibit a melting point of greater than 150~C. Such nanoparticulate compositions can be prepared by ~1 91 aQ-2 W096l00210 ~ ~ V~ wJ~1400 _g_ dispersing the compounds of the invention in a liquid =~
dispersion medium, and wet grinding the compound in the presence of rigid grinding media and a surface modifier to form the nanoparticles. Alternatively, the surface modifier can be contacted with the compound after attrition.
Preferred surface modifiers include nonionic surfactants.
In preferred embodiments, the surface modifier is a high molecular weight nonionic surfactant. Preferred surfactants include poloxamers such as Pluronic_ F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, pol ~mi n~.~, such as Tetronic_ 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, and dialkyl esters of sodium sulfosuccinic acid, such as dioctylsulfosuccinate sodium IDoSS). The concentrations of the surface modifier can vary from about 0.1-75~, preferably 1-60~, and more preferably 10-30~ by weight based on the total c~mhi n~ weight of the contrast agent and surface modifier.
In preferred embodiments, the x-ray contrast composition in the form of surface modified nanoparticles can be associated with a cloud point modifier to further enhance stability during steam heat autoclaving, i.e., the cloud point modifier can reduce particle aggregation during heat sterilization. Preferred cloud point modifiers include nonionic cloud point modifiers, such as polyethylene glycols such as PEG 400, propylene glycol, ethanol, hydroxypropylcyclodextrin and glycerol; ionic cloud point modifiers, such as those described in U.S. Patent No.
5,298,262 including dialkylesters of sodium sulfosuccinic acid such as the dioctylester of sodium sulfosuccinic acid (DOSS); and charged phospholipids, such as diacylphosphatidyl glycerol and dimyristoylphosphatidyl glycerol. The cloud point modifier can be present in an WO96/002l0 2 1 9 1 9 8 3 PCTNS95/07400 .
amount of 0.005-50%, preferably 0.01-30% and more preferably 0.05-20% by weight based on the total weight of the x-ray contrast composition.
The x-ray contrast compositions of this invention comprise the above-described compounds, preferably in the form of partic~es, and a physiologically acceptable carrier therefor. For example, the particles can be dispersed in an aqueous liquid which serves as the carrier for the x-ray contrast agent. Other suitable carriers include liquid carriers such as mixed agueous and nonaqueous solvents, such as alcohol; gels; gases, such as air; and powders.
The x-ray contrast composition can comprise from about 1-99.9, preferably 2-45 and more preferably 10-25% by weight of the above-described particles, the remainder of the composition being the carrier, additives and the like.
Compositions up to about 100% by weight of the particles are contemplated when the composition is in a lyophilized form.
The dose of the contrast agent to be administered can be selected according to techniques known to those 20 skilled in the art such that a sufficient contrast enhancing effect is obtained. Typical doses can range from 20 to 350 mg of iodine per kilogram of body weight of the subject for many imaging applications. For some applications, e.g., lymphography, lower doses, e.g., 0.5-20 mg I/kg, can be 25 effective. For blood pool imaging, the dose can range from 50 to 350 mg of iodine per kilogram of body weight and preferably from 100 to 250 mg of iodine per kilogram of body weight.
The x-ray contrast composition can contain one or more conventional additives used to control and/or enhance the properties~of the x-ray contrast agent. For example, thickening agents such as dextran or human serum albumin, buffers, viscosity regulating agents, suspending agents, peptizing agents, anti-clotting agents, mixing agents, and other drugs and the like can be added. A partial listing of WO96/00210 11- PCT~S95/07400 certain specific additives includes gums, sugars such as dextran, human serum albumin, gelatin, sodium alginate, agar, dextrin, pectin and sodium carboxymethyl cellulose.
Such additives, surface active agents, preservatives and the like can be incorporated into the compositions of the invention.
A method for diagnostic imaging for use in medical procedures in accordance with this invention comprises administering to the body of a test subject in need of an x-ray an effective contrast producing amount of the above-described x-ray contrast composition. In addition to human patients, the test subject can include mammalian species such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, bovine animals and the like. Thereafter, at least a portion of the body containing the administered contrast agent is exposed to x-rays to produce an x-ray image pattern corresponding to the presence of the contrast agent. me image pattern can then be visualized. For example, any x-ray visualization technique, preferably, a high contrast technique such as computed tomography, can be applied in a conventional manner. Alternatively, the image pattern can be observed directly on an x-ray sensitive phosphor screen-silver halide photographic film combination.
The compositions of this invention can be administered by a variety of routes depending on the type of procedure and the anatomical orientation of this tissue being P~; n~d Suitable administration routes include intravascular (arterial or venous) administration by catheter, intravenous injection, rectal administration, subcutaneous administration, intramuscular administration, intralesional administration, intrathecal administration, intracisternal administration, oral administration, administration via inhalation, administration directly into a body cavity, e.g., arthrography, and the like.
Wo96/00210 2 l 9 1 9 8 3 r ~ /400 .
In addition to preferred applications, i.e., for blood pool and lymph node imaging, the x-ray contrast compositions of this invention are also expected to be useful as contrast agents for any organ or body cavity. For example, the compositions of this invention are expected to be useful as angiographic contrast media, urographic contrast media, myelographic contrast media, gastrointestinal contrast media, cholecystographic and cholangiographic contrast media, arthrographic contrast media, hysterosalpingographic contrast media, oral contrast media and bronchographic contrast media.
The following examples further illustrate the invention.
I5 ~x~m~le 1 - Pre~ration of Bis-rl-(ethoxvcarbonvl)~ro~vll 2 4 6-triiodo-5-acetvl~no-iso~ht~late Sodium metal 11.9 g, 82.6 mmole) was dissolved in 500 ml of absolute ethanol followed by the addition of 25 g (42 mmole) of 5-substituted-2,4,6-triiodoisophthalic acid.
After stirring for 30 minutes the solvent was removed under vacuum to give 36.1 g of the ai-sodium salt which was dried under high va-cuum and used without further purification.
To a suspension of the sodium salt (10 g, 15.5 mmole) described above in 50 ml of DMF was added ethyl 2-bromobutyrate and the mixture was stirred at a~bienttemperature for 6 hrs at which point solution was observed After heating for 1 hr on a steam bath, the solution was cooled and adaed to a mixture of ice and water. The desired product crystallized from the aqueous solution overnight and was collected by filtration and dried under vacuum to give an essentially quantitative yield of white solid, mp 195-205~C; CI-MS: MX~830. The lH-NMR (300 MHz) spectral data was consistent with the desired material.
Calculated for C22H26I3NOg: C 31.8~, H 3.16, I 45.92, N
1.69i WO96/002l0 PCT~S95/07400 .
Found: C 31.81, H 3.17, I 45.94; N 1.64.
E~mnle 2 - Pre~aration of Bis-rl-(eth~vcarbonvl)D~ntvll 2,4.6-triiodo-5-ecetvl~m;no-iso~hthalate To a mixture of 5-acetylamino-2,4,6-triiodoisophthalic acid (80 g, 133.1 mmole) and sodium carbonate (28 g, 266.7 mmole~ in dry DME (300 ml) was added ethyl 2-br~m~h~n~te (40.1 ml, 266.7 mmole). After stirring at ambient temperature overnight, the bulk of the solvent was removed under vacuum and the concentrated residue was poured into 4 l of water. The precipitated solid was collected and recrystallized from DMF/water to give 98.5 g of product, mp 118-120~C, after drying at 90~C
under high vacuum. The 1~_NMR (300 MHz) spectral data was 1~ consistent with the desired material.
Calculated for C26H3~I3NOg: C 35.24, H 3.84, I 43.00, N
1.58;
Found: C 35.35, H 3 66, I 43.01, N 1.49.
E~Amnle 3 - Pre~aration of Bis-~1-(ethoxvcarbonvl)ethvll 2 4 6-triiodo-5-acetvl~m;n~-iso~hth~late In a manner similar to the procedures described in Examples 1 and 2 above, analytically pure compound, mp 160-165~C, was prepared. The MS and 300 MHz-NMR spectral data were consistent with the desired product.
Calculated for C2oH22I3No4: C 29.99, H 2.77, N 1.75, I 47.52;
Eound: C 30.11, H 2.65, N 1.72, I 47.40.
E~Amnle 4 - Pre~aration of Bis-rl-(ethoxvcarbonvl)butVll 2.4 6-triiodo-5-acetvl~m;no-iso~hthalate In a manner similar to the procedures described in Examples 1 and 2 above, analytically pure compound, mp 155-156~C, was prepared. The MS and 300 MHz-NMR spectral data were consistent with the desired material.
Calculated for C2~H30I3NO~ C 33.63, H 3.53, N 1.63, I 44.41;
2~91983 WO96/00210 ~ /400 .
Found: C 33.72, H 3.39, N 1.5g, I 44.13 Exam~le 5 - Pre~aration of Bis-~l-(ethoxvcarbonvl)methvll 2 4.6-triiodo-5-acetvlam;no-iso~ht~late In a manner similar to the procedures described in Examples 1 and 2 a~ove, analytically pure compound, mp 194-195~C, was prepared. The MS and 300 MHz-N~R spectral data were consistent with the desired material.
Calculated for ClgHlaI3NOg C 27.97, H 2.35, I 49.25, N 1.87;
Found: C 28.06, H 2.25, I 49.37, N 1.78.
The acids of the above-described esters can be prepared by any conventional techni~ue known in the art.
The acids and salts thereof are particularly useful as wetting agents and/or as surface modifiers in x-ray contrast compositions, particularly nanoparticulate x-ray contrast compositions.
The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.
amount of 0.005-50%, preferably 0.01-30% and more preferably 0.05-20% by weight based on the total weight of the x-ray contrast composition.
The x-ray contrast compositions of this invention comprise the above-described compounds, preferably in the form of partic~es, and a physiologically acceptable carrier therefor. For example, the particles can be dispersed in an aqueous liquid which serves as the carrier for the x-ray contrast agent. Other suitable carriers include liquid carriers such as mixed agueous and nonaqueous solvents, such as alcohol; gels; gases, such as air; and powders.
The x-ray contrast composition can comprise from about 1-99.9, preferably 2-45 and more preferably 10-25% by weight of the above-described particles, the remainder of the composition being the carrier, additives and the like.
Compositions up to about 100% by weight of the particles are contemplated when the composition is in a lyophilized form.
The dose of the contrast agent to be administered can be selected according to techniques known to those 20 skilled in the art such that a sufficient contrast enhancing effect is obtained. Typical doses can range from 20 to 350 mg of iodine per kilogram of body weight of the subject for many imaging applications. For some applications, e.g., lymphography, lower doses, e.g., 0.5-20 mg I/kg, can be 25 effective. For blood pool imaging, the dose can range from 50 to 350 mg of iodine per kilogram of body weight and preferably from 100 to 250 mg of iodine per kilogram of body weight.
The x-ray contrast composition can contain one or more conventional additives used to control and/or enhance the properties~of the x-ray contrast agent. For example, thickening agents such as dextran or human serum albumin, buffers, viscosity regulating agents, suspending agents, peptizing agents, anti-clotting agents, mixing agents, and other drugs and the like can be added. A partial listing of WO96/00210 11- PCT~S95/07400 certain specific additives includes gums, sugars such as dextran, human serum albumin, gelatin, sodium alginate, agar, dextrin, pectin and sodium carboxymethyl cellulose.
Such additives, surface active agents, preservatives and the like can be incorporated into the compositions of the invention.
A method for diagnostic imaging for use in medical procedures in accordance with this invention comprises administering to the body of a test subject in need of an x-ray an effective contrast producing amount of the above-described x-ray contrast composition. In addition to human patients, the test subject can include mammalian species such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, bovine animals and the like. Thereafter, at least a portion of the body containing the administered contrast agent is exposed to x-rays to produce an x-ray image pattern corresponding to the presence of the contrast agent. me image pattern can then be visualized. For example, any x-ray visualization technique, preferably, a high contrast technique such as computed tomography, can be applied in a conventional manner. Alternatively, the image pattern can be observed directly on an x-ray sensitive phosphor screen-silver halide photographic film combination.
The compositions of this invention can be administered by a variety of routes depending on the type of procedure and the anatomical orientation of this tissue being P~; n~d Suitable administration routes include intravascular (arterial or venous) administration by catheter, intravenous injection, rectal administration, subcutaneous administration, intramuscular administration, intralesional administration, intrathecal administration, intracisternal administration, oral administration, administration via inhalation, administration directly into a body cavity, e.g., arthrography, and the like.
Wo96/00210 2 l 9 1 9 8 3 r ~ /400 .
In addition to preferred applications, i.e., for blood pool and lymph node imaging, the x-ray contrast compositions of this invention are also expected to be useful as contrast agents for any organ or body cavity. For example, the compositions of this invention are expected to be useful as angiographic contrast media, urographic contrast media, myelographic contrast media, gastrointestinal contrast media, cholecystographic and cholangiographic contrast media, arthrographic contrast media, hysterosalpingographic contrast media, oral contrast media and bronchographic contrast media.
The following examples further illustrate the invention.
I5 ~x~m~le 1 - Pre~ration of Bis-rl-(ethoxvcarbonvl)~ro~vll 2 4 6-triiodo-5-acetvl~no-iso~ht~late Sodium metal 11.9 g, 82.6 mmole) was dissolved in 500 ml of absolute ethanol followed by the addition of 25 g (42 mmole) of 5-substituted-2,4,6-triiodoisophthalic acid.
After stirring for 30 minutes the solvent was removed under vacuum to give 36.1 g of the ai-sodium salt which was dried under high va-cuum and used without further purification.
To a suspension of the sodium salt (10 g, 15.5 mmole) described above in 50 ml of DMF was added ethyl 2-bromobutyrate and the mixture was stirred at a~bienttemperature for 6 hrs at which point solution was observed After heating for 1 hr on a steam bath, the solution was cooled and adaed to a mixture of ice and water. The desired product crystallized from the aqueous solution overnight and was collected by filtration and dried under vacuum to give an essentially quantitative yield of white solid, mp 195-205~C; CI-MS: MX~830. The lH-NMR (300 MHz) spectral data was consistent with the desired material.
Calculated for C22H26I3NOg: C 31.8~, H 3.16, I 45.92, N
1.69i WO96/002l0 PCT~S95/07400 .
Found: C 31.81, H 3.17, I 45.94; N 1.64.
E~mnle 2 - Pre~aration of Bis-rl-(eth~vcarbonvl)D~ntvll 2,4.6-triiodo-5-ecetvl~m;no-iso~hthalate To a mixture of 5-acetylamino-2,4,6-triiodoisophthalic acid (80 g, 133.1 mmole) and sodium carbonate (28 g, 266.7 mmole~ in dry DME (300 ml) was added ethyl 2-br~m~h~n~te (40.1 ml, 266.7 mmole). After stirring at ambient temperature overnight, the bulk of the solvent was removed under vacuum and the concentrated residue was poured into 4 l of water. The precipitated solid was collected and recrystallized from DMF/water to give 98.5 g of product, mp 118-120~C, after drying at 90~C
under high vacuum. The 1~_NMR (300 MHz) spectral data was 1~ consistent with the desired material.
Calculated for C26H3~I3NOg: C 35.24, H 3.84, I 43.00, N
1.58;
Found: C 35.35, H 3 66, I 43.01, N 1.49.
E~Amnle 3 - Pre~aration of Bis-~1-(ethoxvcarbonvl)ethvll 2 4 6-triiodo-5-acetvl~m;n~-iso~hth~late In a manner similar to the procedures described in Examples 1 and 2 above, analytically pure compound, mp 160-165~C, was prepared. The MS and 300 MHz-NMR spectral data were consistent with the desired product.
Calculated for C2oH22I3No4: C 29.99, H 2.77, N 1.75, I 47.52;
Eound: C 30.11, H 2.65, N 1.72, I 47.40.
E~Amnle 4 - Pre~aration of Bis-rl-(ethoxvcarbonvl)butVll 2.4 6-triiodo-5-acetvl~m;no-iso~hthalate In a manner similar to the procedures described in Examples 1 and 2 above, analytically pure compound, mp 155-156~C, was prepared. The MS and 300 MHz-NMR spectral data were consistent with the desired material.
Calculated for C2~H30I3NO~ C 33.63, H 3.53, N 1.63, I 44.41;
2~91983 WO96/00210 ~ /400 .
Found: C 33.72, H 3.39, N 1.5g, I 44.13 Exam~le 5 - Pre~aration of Bis-~l-(ethoxvcarbonvl)methvll 2 4.6-triiodo-5-acetvlam;no-iso~ht~late In a manner similar to the procedures described in Examples 1 and 2 a~ove, analytically pure compound, mp 194-195~C, was prepared. The MS and 300 MHz-N~R spectral data were consistent with the desired material.
Calculated for ClgHlaI3NOg C 27.97, H 2.35, I 49.25, N 1.87;
Found: C 28.06, H 2.25, I 49.37, N 1.78.
The acids of the above-described esters can be prepared by any conventional techni~ue known in the art.
The acids and salts thereof are particularly useful as wetting agents and/or as surface modifiers in x-ray contrast compositions, particularly nanoparticulate x-ray contrast compositions.
The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.
Claims (11)
1. A compound having the structure ;
wherein Q is n is an integer from 0 to 20;
R1 is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl or acetamidoalkyl;
R2, R3, R4 and R5 are independently H, alkyl, fluoroalkyl, halogen, hydroxy, acylamino, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido;
R6 is alkyl, cycloalkyl, aryl, or aralkyl; and R7 is H or -COR6-
wherein Q is n is an integer from 0 to 20;
R1 is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl or acetamidoalkyl;
R2, R3, R4 and R5 are independently H, alkyl, fluoroalkyl, halogen, hydroxy, acylamino, acetamidoalkyl, cyano, sulfonyl, carboxamido or sulfonamido;
R6 is alkyl, cycloalkyl, aryl, or aralkyl; and R7 is H or -COR6-
2 The compound of claim 1 wherein R1 is alkyl.
3. The compound of claim 1 wherein R5 is H.
4. The compound of claim 1 wherein n is 0, 1, 2, 3, or 4.
5. The compound of claim 1 wherein R2, R3 and R4 are H.
6. The compound of claim 1 wherein R1 is -C2H5.
7. The compound of claim 1 wherein R1 is -C2H5 and R2, R3, R4 and R5 are X.
8. The compound of claim 1 selected from the group consisting of:
Bis-[1-(ethoxycarbonyl)propyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)pentyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)ethyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)butyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)methyl] 2,4,6-triiodo-5-acetylamino-isophthalate.
Bis-[1-(ethoxycarbonyl)propyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)pentyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)ethyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)butyl] 2,4,6-triiodo-5-acetylamino-isophthalate;
Bis-[1-(ethoxycarbonyl)methyl] 2,4,6-triiodo-5-acetylamino-isophthalate.
9. An x-ray contrast composition comprising the compound of claim 1.
10. The x-ray contrast composition of claim 9 further including a pharmaceutically acceptable carrier.
11. A method of medical x-ray diagnostic imaging which comprises administering to the body of a mammal a contrast enhancing effective amount of the x-ray contrast composition of claim 9.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26559094A | 1994-06-24 | 1994-06-24 | |
| US08/265,590 | 1994-06-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2191983A1 true CA2191983A1 (en) | 1996-01-04 |
Family
ID=23011079
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002191983A Abandoned CA2191983A1 (en) | 1994-06-24 | 1995-06-09 | 2,4,6-triiodo-5-substituted-amino-isophthalate esters useful as x-ray contrast agents for medical diagnostic imaging |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5670136A (en) |
| EP (1) | EP0766663A1 (en) |
| JP (1) | JPH10502083A (en) |
| AU (1) | AU2823795A (en) |
| CA (1) | CA2191983A1 (en) |
| FI (1) | FI965094A7 (en) |
| IL (1) | IL114305A0 (en) |
| NO (1) | NO965301D0 (en) |
| WO (1) | WO1996000210A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA72189C2 (en) | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Aqueous suspensions of 9-hydroxy-risperidone fatty acid esters provided in submicron form |
| US6969529B2 (en) | 2000-09-21 | 2005-11-29 | Elan Pharma International Ltd. | Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers |
| US6375986B1 (en) | 2000-09-21 | 2002-04-23 | Elan Pharma International Ltd. | Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate |
| US6270806B1 (en) | 1999-03-03 | 2001-08-07 | Elan Pharma International Limited | Use of peg-derivatized lipids as surface stabilizers for nanoparticulate compositions |
| US6797820B2 (en) * | 1999-12-17 | 2004-09-28 | Vicuron Pharmaceuticals Inc. | Succinate compounds, compositions and methods of use and preparation |
| US7998507B2 (en) * | 2000-09-21 | 2011-08-16 | Elan Pharma International Ltd. | Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors |
| US7198795B2 (en) | 2000-09-21 | 2007-04-03 | Elan Pharma International Ltd. | In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions |
| EP1450863A4 (en) * | 2001-11-07 | 2009-01-07 | Imcor Pharmaceutical Company | VASCULAR IMAGING METHODS COMPRISING THE USE OF NANOPARTICULAR CONTRAST AGENTS |
| AU2003224808A1 (en) * | 2002-03-28 | 2003-10-13 | Imcor Pharmaceutical Company | Compositions and methods for delivering pharmaceutically active agents using nanoparticulates |
| FR3062850B1 (en) * | 2017-02-10 | 2020-01-31 | Guerbet | PROCESS FOR THE MONOTOPE PREPARATION OF ORGANO-IODINE COMPOUNDS |
| FR3084668A1 (en) | 2018-08-02 | 2020-02-07 | Guerbet | PROCESS FOR THE MONOTOPE PREPARATION OF ORGANO-IODINE COMPOUNDS INTERMEDIATE TO THE SYNTHESIS OF IOVERSOL |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2820814A (en) * | 1955-03-21 | 1958-01-21 | Schering Corp | Polyiodinated 5-aminoisophthalic acids, salts, and esters |
| NL239757A (en) * | 1958-06-03 | |||
| US3144479A (en) * | 1958-08-07 | 1964-08-11 | Chemie Linz Ag | New iodine-containing benzoic acid esters |
| DE2909439A1 (en) * | 1979-03-08 | 1980-09-18 | Schering Ag | NEW NON-ionic x-ray contrast agents |
| AU642066B2 (en) * | 1991-01-25 | 1993-10-07 | Nanosystems L.L.C. | X-ray contrast compositions useful in medical imaging |
| US5322679A (en) * | 1992-12-16 | 1994-06-21 | Sterling Winthrop Inc. | Iodinated aroyloxy esters |
| US5344638A (en) * | 1993-03-11 | 1994-09-06 | Sterling Winthrop Inc. | Compositions of iodobenzoic acid derivatives for visualization of the gastrointestinal tract |
| US5264610A (en) * | 1993-03-29 | 1993-11-23 | Sterling Winthrop Inc. | Iodinated aromatic propanedioates |
-
1995
- 1995-06-09 CA CA002191983A patent/CA2191983A1/en not_active Abandoned
- 1995-06-09 AU AU28237/95A patent/AU2823795A/en not_active Abandoned
- 1995-06-09 EP EP95923805A patent/EP0766663A1/en not_active Withdrawn
- 1995-06-09 FI FI965094A patent/FI965094A7/en not_active Application Discontinuation
- 1995-06-09 JP JP8503204A patent/JPH10502083A/en not_active Ceased
- 1995-06-09 WO PCT/US1995/007400 patent/WO1996000210A1/en not_active Ceased
- 1995-06-23 IL IL11430595A patent/IL114305A0/en unknown
-
1996
- 1996-01-16 US US08/586,363 patent/US5670136A/en not_active Expired - Lifetime
- 1996-12-11 NO NO965301A patent/NO965301D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO965301L (en) | 1996-12-11 |
| FI965094L (en) | 1996-12-18 |
| WO1996000210A1 (en) | 1996-01-04 |
| NO965301D0 (en) | 1996-12-11 |
| IL114305A0 (en) | 1995-10-31 |
| US5670136A (en) | 1997-09-23 |
| FI965094A0 (en) | 1996-12-18 |
| EP0766663A1 (en) | 1997-04-09 |
| JPH10502083A (en) | 1998-02-24 |
| AU2823795A (en) | 1996-01-19 |
| FI965094A7 (en) | 1996-12-18 |
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